Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington's disease.

David Moreno-Delgado,Mar Puigdellívol,Antoni Cortés,Jordi Alberch,Sergi Ferré,Vicent Casadó,Paola Gasperini,Carmen Lluís,Enric I Canela,Estefanía Moreno,Peter J Mccormick,Marco Scarselli,Lesley A Howell,Anna Chiarlone,Manuel Guzmán,Silvia Ginés,Joaquín Botta,Mar Rodríguez-Ruiz

doi:10.7554/elife.51093

Abstract

Early Huntington's disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H3R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D1R - H3R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.

Highlights

Huntington’s disease (HD) is a dominant inherited progressive neurodegenerative disorder caused by expansion of a CAG repeat, coding a polyglutamine repeat within the N-terminal region of huntingtin protein (Macdonald, 1993; Vonsattel and DiFiglia, 1998)
To test whether D1R-H3 receptors (H3R) heteromers could be targets for controlling D1R signaling in HD, we first analyzed the expression of both receptors in immortalized striatal cells expressing endogenous levels of full-length wild-type STHdhQ7 or mutant STHdhQ111 huntingtin (Gines et al, 2010)
By proximity ligation assays (PLA), D1R-H3R heteromers were detected as red spots surrounding the blue stained nuclei in both cell types (Figure 1A, left panels of both cell types) and in cells treated with control lentivirus vector (Figure 1—figure supplement 1A) but not in cells depleted of H3R (Figure 1A, right panels of both cell types) by shRNA, as shown by RT-PCR and functionality (Figure 1—figure supplement 1B,C), or in negative controls (Figure 1—figure supplement 1D)

Summary

Introduction

Huntington’s disease (HD) is a dominant inherited progressive neurodegenerative disorder caused by expansion of a CAG repeat, coding a polyglutamine repeat within the N-terminal region of huntingtin protein (Macdonald, 1993; Vonsattel and DiFiglia, 1998). Increased DA levels and DA signaling occur at early stages of the disease (Chen et al, 2013a; Garret et al, 1992; Jakel and Maragos, 2000), resulting in an imbalance in striatal neurotransmission initiating signaling cascades that may contribute to striatal cell death (Paoletti et al, 2008; Ross and Tabrizi, 2011). Several studies with experimental models have changed the traditional view that D2R-MSSNs are more vulnerable in HD (Cepeda et al, 2008; Kreitzer and Malenka, 2007), proposing a new view in which D1R-MSSNs are more vulnerable to the HD mutation In this view, it has been demonstrated that mutant huntingtin enhances striatal cell death through the activation of D1R but not D2R (Paoletti et al, 2008). D1Rs are highly expressed in many tissues (Beaulieu and Gainetdinov, 2011) and broad use of D1R antagonists as a preventive treatment has important drawbacks including locomotor impairments (Gimenez-Llort et al, 1997), or induce depression, parkinsonism and sedation in HD patients (Frank et al, 2008; Huntington Study Group, 2006)

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Conclusion